“AI-associated musculoskeletal syndrome, also known as AIMSS, occurs in up to 50% of AI-treated patients in observational studies, and leads to early treatment discontinuation in up to 20% to 30% of patients. Premature discontinuation of AI therapy can lead to increased likelihood of breast cancer recurrence,” explained Norah Lynn Henry, MD, PhD, Director, Breast Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, who reported these results at the recent San Antonio Breast Cancer Symposium.

Duloxetine is approved for the treatment of fibromyalgia and chronic musculoskeletal symptoms. In a previous open-label phase 2 study, 70% of patients with AIMSS had a 2-point improvement in joint pain on a 10-point scale, which is considered clinically meaningful, she explained.

These phase 2 data led to the current study involving 299 postmenopausal women with stage I to stage III breast cancer who had intermediate to severe pain (a score of 4-10 on a 10-point scale) or worsening pain with AI treatment. The women were randomized to receive duloxetine (30 mg for 1 week, followed by 60 mg for 11 weeks, tapered back to 30 mg) or placebo for 12 weeks of treatment.

Dr Henry explained that the 12-week study period was chosen as an end point because duloxetine has a rapid onset of action and the healthcare provider would know whether a patient was responding by then.

To be enrolled in the trial, patients had to have no contraindications to duloxetine, and not be receiving concurrent selective serotonin reuptake inhibitor treatment or serotonin norepinephrine reuptake inhibitor treatment, which are most often taken for depression. They were stratified according to baseline Brief Pain Inventory pain scores of 4 to 6 and 7 to 10. They were also stratified by previous taxane treatment, which is known to increase musculoskeletal symptoms in patients taking AIs.

Pain questionnaires were completed by patients at weeks 2, 6, 12, and 24.

During treatment, duloxetine was well-tolerated but had more frequent adverse events—including gastrointestinal effects, dizziness, dry mouth, fatigue, and insomnia—compared with placebo.

Of the 299 patients randomized, 127 in the duloxetine group and 128 in the placebo group were evaluable for efficacy. Patients treated with duloxetine had significant reductions in pain scores compared with placebo, a median reduction of 0.82 points more on duloxetine (P = .0002), with responses seen as early as 2 weeks.

The rate of patients who achieved a 2-point difference in Brief Pain Inventory pain score (ie, clinically significant change from baseline) favored duloxetine over placebo; 54% versus 44% at 2 weeks; 69% versus 49% at 6 weeks; and 69% versus 60% at 12 weeks. By 24 weeks, however, the difference between the groups was gone, with 60% and 59% experiencing a 2-point improvement from baseline with duloxetine and placebo, respectively.

The odds of improving pain with duloxetine were 1.69, and patients receiving duloxetine were 3.8 times more likely to experience improved joint stiffness than those receiving placebo.

The duloxetine group saw a modest improvement in nonpain-related quality of life, but no difference in depression was seen between groups.

“These findings are consistent with other studies of duloxetine. The mechanism by which duloxetine improves pain is poorly understood,” Dr Henry said.

Dr Ganz said that the trial Dr Henry presented was well-conducted and enrolled only women with substantial pain.

“There was an astounding placebo response, and we would like to have an explanation for that,” she said.

“It is clear that duloxetine relieved pain, but the effect was small compared with placebo, with increased adverse events and cost. The message to take back to the clinic is to possibly consider a short-term trial of duloxetine in patients who may be having multiple AI-related symptoms,” Dr Ganz stated.